Common genetic variants improve risk stratification after atrial switch operation for transposition of the great arteries. (14th October 2021)

• Record Type: Journal Article
• Authors: Woudstra, O; Skoric-Milosavljevic, D; Post, M C; Meijboom, F J; Jongbloed, M R M; Van Dijk, A P J; Konings, T C; Bezzina, C R; Mulder, B J M; Bouma, B J; Tanck, M W T
• Is Part Of: European heart journal. Volume 42(2021)Supplement 1
• Publication Date: 2021-10-14
• Subjects: Epidemiology, Prognosis, Outcome; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehab724.1855
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: Background: Current clinical risk scores are able to predict late complication risk in adults after atrial switch operation (AtrSO) for transposition of the great arteries (TGA), but a large heterogeneity in clinical course remains. Purpose: To study whether common genetic factors are predictive of outcome and provide added value to an existing clinical risk score in TGA-AtrSO patients. Methods: This multicenter study examined the association of genome-wide single-nucleotide polymorphisms (SNPs) in TGA-AtrSO patients with a combined clinical endpoint: time to symptomatic ventricular arrhythmia, heart failure hospitalization, ventricular assist device implantation, heart transplantation, or mortality. Furthermore, we evaluated whether a polygenic risk score (PRS) constructed of independent single-nucleotide polymorphisms (SNPs) with a p<1x10–5 could be of added value to a recently published clinical risk score (included clinical factors: age >30 years, prior ventricular arrhythmia, age >1 year at repair, ≥moderate right ventricular dysfunction, severe tricuspid regurgitation, and ≥mild left ventricular dysfunction). Results: We followed 133 patients (age at inclusion 28 [IQR 24–35] years, 59% male) for 13 [IQR 8–16] years. Thirty-two patients (24%) reached the endpoint. The genome-wide association study yielded one locus that reached genome-wide significance (p<1x10 –8 ) and 18 loci marked by 20 SNPs that reached the suggestive threshold (p<1x10 –5 ). The constructed PRS remained an independent predictor after correction for the clinical score (HR=1.21/point increase [95% CI 1.13–1.29], p=3x10 –10 ). While the clinical risk score indicated intermediate (5–20%) 5-year risk of events in 52 patients (39%), the combined risk score (clinical score + PRS) reclassified 35 patients to low (<5%) and 6 to high (>20%) risk. Observed 5-year event-free survival based on the combined score remained 100% for low-risk patients, compared to 23% and 64% in intermediate and high-risk patients, respectively. This resulted in improved risk stratification with the combined risk score vs the clinical risk score alone (p=2x10 –16, C-statistic 0.95 vs 0.85). Conclusions: Genetic factors explain some of the variation in clinical course of TGA-AtrSO patients and improve risk stratification. In the heterogeneous group of patients with a clinical score indicating intermediate risk, the combined model could classify 67% of patients more accurately to <5% or >20% risk. These data argue for more research into the impact of genetics on clinical outcome in adult congenital heart disease. FUNDunding Acknowledgement: Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation